A major obstacle to AIDS vaccine and therapeutic development is the incomplete understanding of what constitutes protective immunity to HIV-1. We are continuing to study the role of humoral and cellular immunity in preventing HIV infection and we are investigating the immune response to HIV in infected patients. Using model viral culture systems designed to support primary HIV isolates, we observe that infected individuals carry a quasispecies of viruses which have different antibody neutralization sensitivities. In general, isolates with tropism for macrophages are antibody resistant, while T cell tropic isolates show increased antibody sensitivity. Late stage patients harbor HIV isolates which are resistant to antibodies, independent of the virus phenotype. Our data demonstrate that virus neutralization and escape from antibodies depends on antibody repertoire, virus phenotype and virus variation. In the last year, we initiated studies on heterosexual virus transmission and are applying and developing assays to measure antiviral activity of vaginal products on primary viruses. We also initiated projects on the cellular immune response to HIV and are finding that patients even late in disease have the ability to generate MHC-restricted effector cells against viral proteins.